Abstract
IntroductionThe age of diagnosis of Huntington's disease (HD) varies among individuals with the same HTT CAG-repeat expansion size. We investigated whether early-life events, like perinatal insults or neurodevelopmental disorders, influence the diagnosis age. MethodsWe used data from 13,856 participants from REGISTRY and Enroll-HD, two large international multicenter observational studies. Disease-free survival analyses of mutation carriers with an HTT CAG repeat expansion size above and including 36 were computed through Kaplan-Meier estimates of median time until an HD diagnosis. Comparisons between groups were computed using a Cox proportional hazard survival model adjusted for CAG-repeat expansion length. We also assessed whether the group effect depended on gender and the affected parent. ResultsInsults in the perinatal period were associated with an earlier median age of diagnosis of 45.00 years (95%CI: 42.07–47.92) compared to 51.00 years (95%CI: 50.68–51.31) in the reference group, with a CAG-adjusted hazard ratio of 1.61 (95%CI: 1.26–2.06). Neurodevelopmental disorders were also associated with an earlier median age of diagnosis than the reference group of 47.00 years (95% CI: 43.38–50.62) with a CAG-adjusted hazard ratio of 1.42 (95%CI: 1.16–1.75). These associations did not change significantly with gender or affected parent. ConclusionsThese results, derived from large observational datasets, show that perinatal insults and neurodevelopmental disorders are associated with earlier ages of diagnosis of magnitudes similar to the effects of known genetic modifiers of HD. Given their clear temporal separation, these early events may be causative of earlier HD onset, but further research is needed to prove causation.
Highlights
The age of diagnosis of Huntington's disease (HD) varies among individuals with the same huntingtin protein (HTT) CAG-repeat expansion size
We further examined whether associations depend on the gender of the participants or the gender of the affected parent, since it is possible that these may influence any relationship with early life events and age of diagnosis in HD
The baseline characteristics of the reference groups were homogeneous for REGISTRY and Enroll-HD cohorts, and both were composed for the great majority of Caucasian participants (Table 2)
Summary
The age of diagnosis of Huntington's disease (HD) varies among individuals with the same HTT CAG-repeat expansion size. Neurodevelopmental disorders were associated with an earlier median age of diagnosis than the reference group of 47.00 years (95% CI: 43.38–50.62) with a CAGadjusted hazard ratio of 1.42 (95%CI: 1.16–1.75) These associations did not change significantly with gender or affected parent. Conclusions: These results, derived from large observational datasets, show that perinatal insults and neurodevelopmental disorders are associated with earlier ages of diagnosis of magnitudes similar to the effects of known genetic modifiers of HD. Given their clear temporal separation, these early events may be causative of earlier HD onset, but further research is needed to prove causation. Identifying environmental modifiers which may be targeted to delay the age of onset in pre-manifest gene expansion carriers (GEC) is critical to reducing the burden of HD
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